USP19 as a Novel Therapeutic Target for Impeding Propagation and Secretion of Tau in Parkinson s Disease
Abstract
Parkinson s disease (PD) is a devastating neurodegenerative disorder affecting over 2% of the worldwide population. Yet, since the discovery of L-DOPA in the 1960s, there have been no new advances in the development of disease-modifying therapies despite increasing knowledge of the genetics and mechanisms that can cause this disorder. Thus, it is imperative that we develop new treatments for PD or face an impending epidemic, a scenario which requires us and the field to take some bold risks now. Recent studies have started to shed some light on a potential new pathway that we believe holds great promise for therapy. In PD and other degenerative disorders, such as Alzheimer s disease and ALS, classical hallmarks of these disorders are a progressive loss of cells from the brain, and an accumulation of protein clumps, which in PD are termed Lewy bodies (LBs). LBs are observed early in the development of PD, and imaging studies have shown that these LBs can move throughout the brain ultimately leading to a loss of cells within the brains of PD patients. These clumps can be found in many other neurodegenerative disorders, albeit comprised of different components. In PD, the protein that is the predominant component is alpha-synuclein (alpha-syn). In Alzheimer s disease, and other diseases with dementia, tau is one of the main proteins in these clumps. Intriguingly, these diseases overlap, as tau is observed in LBs in PD, and mutations in the gene encoding tau have been associated with PD. Thus, we believe that tau and alpha-syn are spread throughout the brain, seeding new clumps that move from cell to cell, causing damage and cell loss. Thus, preventing the spread of these toxic protein clumps represents an attractive therapeutic approach and indeed several groups now have early-stage molecules and immunotherapies to prevent the spread of these clumps. However, most of these strategies are aimed at preventing cells from taking up the protein clumps. We propose an alternative strategy, which is to prevent the release of the proteins in the first place, so that by remaining in the cell, new clumps cannot be seeded and the machinery of the cells can destroy the clumps that remain inside. This is a novel approach and has not been tested before, and it stems from recent work delineating a novel protein release pathway in which proteins that become dysfunctional within the cell, such as alpha-syn and tau, are actively released where they can be taken up by neighbouring cells. Central to this pathway is the enzyme USP19 whose activity can promote the release of these proteins that have become dysfunctional. USP19 is druggable and, indeed, through partnerships with academic and industry groups we now have two promising inhibitors against USP19, which we believe will strongly reduce the spreading of tau and alpha-syn thereby pointing towards a new neuroprotective strategy for PD. To test this idea, in this application we propose using two distinct models. In the first model, mice are injected with tau and alpha-syn directly into the brain, leading to an accumulation of their clumps throughout the brain. In our second model, we have decided that we should use human cells to model human disease and therefore will work with patient-derived human stem cells. These induced pluripotent stem cells (iPSCs) were generated either from skin or blood from humans and, with the correct recipe of ingredients, these stem cells can be made into cell types found within the human brain. However, we propose taking these cells one step further, and rather than growing them in the conventional 2D cell culture dish, we will grow and mature these stem cells into what we term 3D "mini-brains". Through work in our groups, we can generate these mini-brains, also called neuronal organoids, to be representative of the region affected in PD. Using this human model, combined with the mouse model, we will perform a comprehensive study of tau and alpha-syn and their
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810808
Entities
People
- Simon Wing
Organizations
- McGill University Health Centre
- United States Army